A growing body of data implicates Wnts in tumorigenesis. Severnal Wnts have been identified as oncogenes in murine mammary tumor models. Furthermore, overexpression incidence of mammary tumors in vivo; inhibition of Wnts with antisense reverses the transformed phenotype. Thus, it seems likely that Wnts are involved in at least a subset of mammary tumors. Wnts signal through members of the Frizzled family of proteins and soluble Frizzled-related proteins (FRPs) have been shown to act as Wnt antagonists. Evidence from our lab and others indicates that reduced expression of FRP may be linked to mammary epithelial cell transformation/tumorigenesis. To further test the hypothesis that Wnts play a casual role in mammary epithelial transformation/tumorigenesis and to assess the ability of Wnt inhibitors to reverse this phenotype, we will assess the effect of extracellular and intracellular Wnt inhibitors on mammary epithelial cell transformation/tumorigenesis. In addition, we propose to apply a well-established Xenopus development assay, which is highly sensitive to the actions of Wnts, to identify novel inhibitors of Wnt signaling in mammary epithelium. Results of these studies will provide insight into the role that Wnts play in mammary tumorigenesis, will assess the ability of Wnt signaling inhibitors to reverse the transformed phenotype and will identify novel endogenous antagonists of Wnt signaling.